Diffuse large B-cell lymphoma associated with chronic inflammation
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| Diffuse large B-cell lymphoma associated with chronic inflammation | |
|---|---|
| Other names | Epstein–Barr virus-associated diffuse large B cell lymphoma associated with chronic inflammation; pyothorax-associated lymphoma |
| Specialty | Hematology, oncology |
| Symptoms | Pain at tumor sites |
| Complications | Spread to other tissues |
| Diagnostic method | Histology of biopsied tissue |
| Prognosis | Guarded |
| Frequency | Rare |
Diffuse large B-cell lymphoma associated with chronic inflammation (DLBCL-CI) is a subtype of the Diffuse large B-cell lymphomas and a rare form of the Epstein–Barr virus-associated lymphoproliferative diseases, i.e. conditions in which lymphocytes infected with the Epstein-Barr virus (EBV) proliferate excessively in one or more tissues. EBV infects ~95% of the world's population to cause no symptoms, minor non-specific symptoms, or infectious mononucleosis. The virus then enters a latency phase in which the infected individual becomes a lifetime asymptomatic carrier of the virus. Some weeks, months, years, or decades thereafter, a very small fraction of these carriers, particularly those with an immunodeficiency, develop any one of various EBV-associated benign or malignant diseases.[1]
The EBV-associated diseases include: 1) some cases of non-lymphoproliferative disorders such as the Alice in Wonderland syndrome,[2] cerebellar ataxia, particularly childhood cases of this disorder,[3] and two autoimmune diseases, multiple sclerosis and systemic lupus erythematosis;[4][5][6][7] 2) non-lymphoid cancers such as EBV+ gastric cancer,[8] most if not all cases of nasopharyngeal cancer, and some cases of soft tissue sarcoma and leiomyosarcoma;[9] and 3) Epstein-Barr virus-associated lymphoproliferative diseases such as chronic active EBV infection, EBV+ hemophagocytic lymphohistiocytosis, EBV+ Burkitt lymphoma,[1] EBV+ Hodgkin lymphoma,[10] and the EBV+ diffuse large B-cell lymphomas which include as a subtype, DLBCL-CI.[1]
DLBCL-CI is a highly aggressive malignancy that most commonly afflicts elderly males. In this disease, EBV-infected B-cell lymphocytes located in sites of chronic inflammation that are walled off from the immune system proliferate excessively, acquire pro-malignant gene changes, and eventually form a tumor mass. The historically most common form of DLBCL-CI, often termed pyothorax-associated lymphoma (PAL), exemplifies this disease. PAL develops in grossly inflamed pleural cavities may years after a pneumothorax is medically induced to collapse a lobe or entire lung in order to treat pleurisy[11] caused by an otherwise uncontrollable inflammatory condition, usually (i.e. ~80% of all PAT cases[12]) pulmonary tuberculosis. The pleural cavity and the inflammatory pus within it are thought to protect the EBV-infected B-cells from immune attack. Given the decline in the occurrence of chronic pleural tuberculosis and the virtual abandonment of therapeutic pneumothorax to treat chronic pleural inflammation, PAT is rarely encountered today. Currently, DLBCL-CI is diagnosed in other sites of chronic inflammation that are or appear to be sequestered from the immune system such as infected joints and bones or areas in and around foreign bodies.[13]
In 2017, the World Health Organization provisionally included Fibrin-associated diffuse large B cell lymphoma (FA-DLBCL) as a form of DLBCL-CI.[13] Similar to DLBCL-CI, FA-DLBCL is a diffuse large B-cell lymphoma that arises in immunologically sequestered sites (e.g. body cavities, foreign bodies). Unlike DLBCL-CI, however, FA-DLBCL most commonly develops in sites where fibrin, a breakdown product of the blood clotting factor, fibrinogen, forms and deposits on the abnormal tissues in body cavities or around foreign bodies. FA-DLBCL also differs from DLBCLCI in that it usually presents as infiltrates rather than tumors and is a far less aggressive and in many cases a relatively benign disease.[14] Here, it is considered in the differential diagnosis of DLBCL-CI and more fully described elsewhere (see fibrin-associated diffuse large B-cell lymphoma).
Individuals presenting with the PAL form of DLBCL-CI have typically been elderly males (male to female ratio 4:1[15] to 12:1[16]) with a median age of 67 years (range 46–86 years).[12] Most of these individuals have been Japanese with a long (median 37 years) history of pyothorax due to tuberculosis previously treated with a pneumothorax.[16] However, uncommon cases of PAT have been reported in Western Countries, in non-Japanese individuals, in individuals who were not threatened with a pneumothorax, and/or in individuals who had other causes than tuberculosis for their pyothorax.[17] Patients with PAL commonly present with back[12] and/or chest pain, coughing, fever, shortness of breath, and radiological evidence of a pleural space tumor[16] which may be very large.[15] The tumor may extend into the chest wall, ribs, lung tissue, lymph nodes of the mediastinum, and diaphragm[15] but usually has not disseminated beyond these areas, i.e. examinations of the peripheral blood, bone marrow, and distal lymph nodes typically do not show evidence of the disease.[12] Individuals with non-PAL forms of DLBCL-CI present with tumorous growths in or around bone infections, skin ulcers, venous ulcers, metallic implants, artificial heart valves,[15] intrauterine birth control devices, and implanted surgical mesh.[16] The presentation of these cases is similar to that of PAL: afflicted individuals are most often middle-aged or elderly males who have a long-standing (almost always >10 years) history of inflammation, have recently developed pain and localized swelling, and on radiological examination have a discrete, sometimes large, tumor mass at the involved site.[15]
Pathogenesis
DLBCL-CI develops in closed spaces which are or may be sequestered from the immune system; these spaces allow the survival and growth of cancer cells because they are cut off from the circulation and have decreases in various components of the immune system such as cytotoxic T-cells.[14] The neoplastic B-cells in these spaces carry the EBV virus in stage III latency (see EBV latency infections) and therefore express the following viral products:[1] 1) Epstein–Barr virus nuclear antigen 2 (EBNA-2) (a protein which stimulates infected cells to make >300 gene products some of which,[1] e.g. the protein product of the MYC proto-oncogene, Myc, promote these cell's proliferation, survival, and malignancy);[18] 2) two Epstein–Barr virus-encoded small RNAs, EBER 1 and 2, which cause infected cells to produce interleukin 6 (a protein that stimulates these cells to proliferate) and interleukin 10 (a protein that helps these cells avoid attack by host cytotoxic T-cells[1] and also blocks their apoptosis responses thereby prolonging their survival);[16] and 3) LMP1, a protein that regulates the infected cells' maturation and promotes their expression of NF-κB and BCL2 (which are cell signaling proteins that block the infected cells apoptosis responses and stimulates their proliferation).[18] The neoplastic cells in this disease also show mutations in their p53 tumor suppressor gene, deletion of the TNFAIP3 gene (whose product protein inhibits NF-κB activation), and abnormalities in the expression of other genes.[17] DLBCL-CI therefore appears to be a lymphoma that is driven by EBV-induced changes in the expression of various genes that regulate the malignant behavior of the B-cells which it infects.[12] The development and progression of this disease depends on its development in an environment that affords protection from the immune system.[14] And, the neoplastic B-cells in this disease are activated B-cells (i.e. ABC).[15] DLBCL subtypes caused by ABC are far more aggressive than those caused by other B-cell types, i.e. germinal center B-cells (GBC) or unclassifiable B-cells. The ABC basis of DLBCL-CI likely contributes to its aggressiveness.[15]